Beta-caryophyllene is a dietary cannabinoid

TLDR

Cannabis-derived psychoactive cannabinoids and endocannabinoids bind CB1 and CB2 receptors; while CB1 mediates psychotropic effects, CB2 activation is a therapeutic target for inflammation, pain, atherosclerosis, and osteoporosis, and the volatile compound (E)-beta‑caryophyllene is a common constituent of many food and spice plant oils and Cannabis. Molecular docking shows (E)-beta‑caryophyllene binds the CB2 receptor at a site involving pi‑pi stacking with residues F117 and W258. The study demonstrates that (E)-beta‑caryophyllene is a selective, nonpsychoactive CB2 agonist with an ICi of 155 nM that inhibits adenylate cyclase, induces calcium transients, modestly activates Erk1/2 and p38, suppresses LPS‑induced cytokine production and Erk1/2/JNK1/2 phosphorylation in monocytes, and orally reduces carrageenan‑induced inflammation in wild‑type but not CB2‑deficient mice, confirming its anti‑inflammatory cannabimimetic activity.

Abstract

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.